Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression

Paolo Devanna, Maartje van de Vorst, Rolph Pfundt, Christian Gilissen, Sonja C Vernes

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3'UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3'UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability.

Original languageEnglish
Pages (from-to)717-721
Number of pages5
JournalHuman Genetics
Issue number9
Early online date10 Aug 2018
Publication statusPublished - Sept 2018


  • 3' Untranslated Regions/genetics
  • Cohort studies
  • Gene expression regulation
  • Genetic variation
  • Genome, human
  • Humans
  • Intellectual Disability/genetics
  • microRNAs
  • Sequence analysis, DNA/methods


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